Exercise pulmonary hypertension in patients with systemic sclerosis based on updated guidelines

Recent European guidelines have introduced the concept of exercise pulmonary hypertension (ex-PH). However, the clinical characteristics of ex-PH in systemic sclerosis (SSc) remains unknown. We aimed to investigate the characteristics of exercise pulmonary hypertension (ex-PH) in patients with systemic sclerosis (SSc), which are unknown. We retrospectively examined 77 patients with SSc who underwent symptom-limited exercise testing using a cycle ergometer with right heart catheterization at our hospital. Nineteen patients with postcapillary PH were excluded. Fifty-eight patients (median age, 63 years; 55 women) were divided into the overt-PH (n = 18, mean pulmonary arterial pressure [PAP] > 20 mmHg and pulmonary vascular resistance > 2 Wood units at rest), ex-PH (n = 19, mean PAP/cardiac output slope > 3), and non-PH (n = 21) groups. Exercise tolerance and echocardiography results were compared among the groups. Peak oxygen consumption was high in the non-PH group, intermediate in the ex-PH group, and low in the overt-PH group (14.5 vs. 13.0 vs. 12.5 mL/kg/min, p = 0.043), and the minute ventilation/peak carbon dioxide production slope was also intermediate in the ex-PH group (32.2 vs. 32.4 vs. 43.0, p = 0.003). The tricuspid annular plane systolic excursion/systolic PAP ratio decreased from non-PH to ex-PH to overt-PH (0.73 vs. 0.69 vs. 0.55 mm/mmHg, p = 0.018). In patients with SSc, exercise PH may represent an intermediate condition between not having PH and overt PH, according to the new guidelines.


Echocardiographic parameters
Echocardiographic parameters in the groups are summarized in Table 3.Among the echocardiographic parameters, the TASPE/systolic PAP (sPAP) ratio was significantly different among the three groups (non-PH vs. ex-PH Figure 1.Flowchart of patients with SSc who underwent cardiopulmonary exercise testing with right heart catheterization.CO, cardiac output; ex-PH, exercise pulmonary hypertension, mPAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; SSc, systemic sclerosis.

Discussion
We have elucidated the impact and characteristics of the exercise PH in the context of the new definition.Most patients who would be diagnosed with borderline PH according to the old definition had ex-PH and were reclassified as overt-PH under the new definition.Based on the results of the 6-min walk test (6MWT) and CPX, exercise tolerance in the ex-PH group was intermediate, between those of the non-PH and overt-PH groups.In addition, the tricuspid annular plane systolic excursion (TAPSE)/sPAP ratio upon echocardiography, which is an RV-pulmonary arterial coupling index, was also intermediate in the ex-PH group.Exercise testing with RHC is necessary for the diagnosis of ex-PH, and assessments with other non-invasive tests remain to be developed.
Monitoring and assessment of these parameters may contribute to the early detection and management of PH in patients with SSc, which could improve their clinical outcomes and quality of life.Further research is warranted to validate these results and explore their clinical implications in larger patient cohorts.

Exercise tolerance
In the context of SSc, CPX is a valuable non-invasive tool for the detection of PH.In a previous report, a peak VO 2 of 18.7 mL/kg/min or higher was effective to rule out SSc-PH, with a high negative predictive value 28 .
Similarly, in our study, exercise tolerance indicators, such as 6MWD and peak VO 2 , were gradually decreased from a non-PH state to ex-PH and overt-PH.However, exercise tolerance in patients with SSc is influenced by several factors and does not reflect hemodynamics alone 19 .In our current study, even patients with SSc without PH had a 6MWD of 436 m and peak VO 2 of 14.5 mL/kg/min, corresponding to the "intermediate risk" category in the comprehensive risk assessment 13 .Importantly, exercise tolerance is generally lower in patients with SSc, who are predominantly older, than in those with other forms of PH.It is well recognized that SSc, as a systemic disease, leads to reduced exercise capacity due to peripheral/muscular limitations and impaired tissue oxygen extraction 19,20 .Unlike peak VO 2 , which is a measure of maximal load, the 6MWD is a measure of submaximal load and is affected by multifactorial exercise intolerance, such as peripheral effects, which may be one reason for the lack of statistically significant differences in 6MWD among the groups in our study.
The elevated VE vs. VCO 2 slope in our study indicates abnormal ventilation/perfusion matching and increased dead space ventilation, both of which are associated with pulmonary vascular dysfunction and impaired gas exchange 29 .Previous reports also suggest that indicators of ventilatory inefficiency such as VE vs. VCO 2 slope are useful for detecting PH in SSc, and our results similarly positioned ex-PH between non-PH and overt-PH 28 .Unlike peak VO 2 , the VE vs. VCO 2 slope in ex-PH corresponds to the "low risk" category in the PH risk classification guidelines 13 .Because the VE vs. VCO 2 slope can be evaluated even at submaximal effort, it may provide a more accurate assessment of risk category than 6MWD and peak VO 2 , which are sensitive to deconditioning in SSc.

TAPSE/sPAP ratio
The invasive nature of exercise stress testing with RHC poses a challenge owing to the limited availability of facilities capable of performing the test.In contrast, echocardiography is a non-invasive and effective screening tool.
In the recent ESC/ERS guidelines for PH, the established cut-off values for PH screening and key echocardiographic parameters did not change substantially.However, a novel indicator of PH, the TAPSE/sPAP ratio, was introduced 13 .This ratio combines measures of RV function and pulmonary artery indices, easily assessable via standard echocardiography, serving as an estimate of RV-pulmonary artery coupling 30 .In PH, progressive pulmonary vascular remodeling augments the load on the contracting RV, consequently modifying RV-pulmonary arterial coupling.A cut-off value of the TAPSE/sPAP ratio for PH screening has been proposed based on a cohort study 31 , leading to its inclusion as a screening indicator in the updated guidelines.More recent studies have demonstrated its utility in risk stratification and prognostication of patients with PH, including those with SSc 32,33 .In the SSc EUSTAR cohort, a TAPSE/sPAP ratio < 0.55 mm/mmHg was identified as a risk factor for PH 34 .
In our study, the TAPSE/sPAP ratio effectively differentiated ex-PH from non-PH and overt-PH.This suggests its potential as an early detection marker for SSc-PH.In our cohort, the TAPSE/sPAP ratio was 0.66 mm/mmHg for ex-PH compared to 0.54 mm/mmHg for overt-PH.Furthermore, in SSc, the TAPSE/sPAP ratio reportedly correlates with peak VO 2 and the VE vs. VCO 2 slope, parameters derived from CPX, supporting our results that CPX parameters and the TAPSE/sPAP ratio are associated with hemodynamic severity 35 .
This study had several limitations.It was a retrospective, single-center study, including a relatively small sample size; therefore, the statistical power may not have been sufficient to detect negative outcomes.The study population did not include patients with overt or occult left ventricular diastolic dysfunction.Additionally, some patients with SSc were unable to undergo exercise stress tests owing to orthopedic issues, sarcopenia, and other factors, leading to their exclusion from the study.Our cohort was exclusively Japanese and comprised older and predominantly female patients; therefore, the results of this study may not be generalizable to younger adults or men.Age is known as an important confounder of the pulmonary vascular response during exercise and exercise tolerance, such as peak VO 2 and 6MWD.
The definition of exercise PH has been established, and its association with poor prognosis in the population, including patients with SSc, is well-known 23,36,37 .However, the prognostic impact of the updated definition, where borderline PH (mean PAP: 21-24 mmHg) is now classified as overt PH, remains unclear.Assessing its prognostic impact requires long-term observation and further research exploration.

Study participants
In this retrospective, cross-sectional study, we examined consecutive patients with SSc who exhibited dyspnea during exertion, performed owing to suspected or confirmed PH, and who underwent CPX with RHC at our hospital from 2013 to 2022.Definitions of SSc were based on the American College of Rheumatology diagnostic criteria 38 .This study was approved by the Committee for Clinical Studies and Ethics of Kyorin University School of Medicine.The purposes and risks of the study were explained to the patients, who provided informed consent prior to participating.All methods were performed in accordance with the relevant guidelines and regulations.

RHC and CPX
RHC was performed with a 6-F, double-lumen, balloon-tipped, flow-directed Swan-Ganz catheter (Harmac Medical Products, Inc., Buffalo, NY, USA) via a transjugular approach, as previously described 39 .Baseline hemodynamic data were recorded, and the zero-reference level (mid-chest) was adjusted at the start of pressure measurement.Measurements were obtained at the end of normal expirations with patients in the supine position to assess the right ventricular pressure, mean PAP, sPAP, diastolic PAP, and PAWP.Incremental, symptom-limited CPX was performed with patients in the supine position by using an electromagnetically braked cycle ergometer (Nuclear Imaging Table with Angio Ergometer; Lode BV, Groningen, The Netherlands) and the ramp protocol.The test comprised a 3-min rest period, followed by 3-min warm-up at an ergometer setting of 10 W (60 rpm), and testing with 1-W increase in exercise load every 6 s (totaling 10 W/ min).During the exercise, VO 2 , VCO 2 , and VE were measured using a metabolic cart (Cpex-1; Inter Reha Co. Ltd., Tokyo, Japan).Peak VO 2 was calculated as the average value obtained during the last 30 s of exercise.The VE vs. VCO 2 slope was calculated from the start of incremental exercise to the respiratory compensation point by using least-squares linear regression.
Heart rate, arterial blood pressure directly recorded in the radial artery, and electrocardiogram were monitored continuously during the test.PAP and PAWP in the RHC were measured every minute.We used the averaged mean PAP and mean PAWP during several-second periods rather than end-expiratory measurements during exercise.SaO 2 and the pulmonary artery (SvO 2 ) were measured at rest and during warm-up, submaximal, and peak exercise.CO was determined via the Fick method, using the following formula: CO (L/min) = VO 2 / [1.34 × hemoglobin concentration (Hb) × (SaO 2 − SvO 2 )].The arterial mixed venous oxygen content difference was calculated as follows: 13.4 × Hb × (SaO 2 − SvO 2 )/1000.Pulmonary vascular resistance (PVR) and pulmonary arterial compliance (PAC) were calculated as: PVR (Wood units) = (mean PAP -PAWP)/CO and PAC = stroke volume/pulse pressure.The mean PAP/CO slope was calculated from multipoint plots of the mean PAP and CO by using least-squares linear regression 40 .
The 6MWT was performed according to American Thoracic Society guidelines without supplemental O 2 one day before RHC 41 .

Echocardiography
A transthoracic Doppler echocardiogram was obtained with the patient in the resting state and digitally stored on an Artida (Toshiba, Tokyo, Japan) or EPIQ (Philips Healthcare, Cambridge, MA USA) ultrasound system within 3 months of the RHC.Left ventricular ejection fraction was calculated using Simpson's biplane method in the apical four-and two-chamber views.Left atrial volume was measured in the same way and was indexed according to body surface area.Mitral inflow was assessed in the apical four-chamber view with the pulsed-wave Doppler sample volume placed at the tips of the mitral valve leaflets during diastole; accordingly, the early (E) and late peak diastolic velocities of the mitral inflow and the E-wave deceleration time were measured.Mitral annular motion was assessed using pulsed-wave tissue Doppler imaging with the sample volume placed in the septal (e' septal).Subsequently, the E/e' ratio was calculated.Tricuspid regurgitation peak velocity and inferior vena cava diameter (right atrial pressure estimation) were used to calculate sPAP by using the Bernoulli equation in the absence of laminar tricuspid regurgitation and/or pulmonary stenosis.The RV systolic function was assessed by measuring TAPSE.Subsequently, the TAPSE/sPAP ratio was calculated.The RV end-diastolic area (RVEDarea) and endsystolic area (RVESarea) were assessed via manual planimetry in the apical four-chamber view, and the RV fractional area change (RVFAC) was derived using the formula: RVFAC = [(RVEDarea-RVESarea)/RVEDarea] × 100.

Hemodynamic definitions
Based on the 2022 ESC guidelines 13 , patients with SSc were divided into three different groups according to their resting and exercise hemodynamics: 1) overt PH (mean PAP at rest > 20 mmHg and PVR at rest > 2 Wood units; 2) exercise PH (ex-PH, mean PAP/CO slope > 3 mmHg/L/min); and 3) non-PH (without PH) groups.

Statistical analysis
Continuous variables are presented as mean ± standard deviation or medians (25 th quartile, 75 th quartile).The Shapiro-Wilk test and histogram analyses were performed to assess datasets for normality.Comparisons of more than two groups were performed using a one-way analysis of variance (with the Tukey post-hoc test) or the Kruskal-Wallis test (with Dunn's post-hoc test), as appropriate.Categorical variables are presented as frequencies (percentages) and were compared using the Fisher's exact test or Pearson's χ 2 test.Analyses were performed using SPSS Statistics for Windows (version 26.0;IBM Corp., Armonk, NY, USA).
https://doi.org/10.1038/s41598-024-63823-0www.nature.com/scientificreports/In conclusion, in patients with SSc, exercise PH may represent an intermediate condition between not having PH and overt PH, according to the new guideline definitions.

Table 1 .
Baseline characteristics of the included patients.Values are reported as mean ± standard deviation or medians (interquartile ranges) or n (%).BMI body mass index, BNP brain natriuretic peptide, DLCO/VA % predicted, diffusing capacity of the lung for carbon monoxide, normalized according to alveolar volume, ERA endothelin receptor antagonist, ex-PH exercise pulmonary hypertension, PAP pulmonary arterial pressure, PAWP pulmonary arterial wedge pressure, PDE5i phosphodiesterase type V inhibitor, PH pulmonary hypertension, PVR pulmonary vascular resistance, RAP right atrial pressure, SaO 2 O 2 saturation in arterial blood, SGCSs soluble guanylate cyclase stimulator, SvO 2 O 2 saturation in the pulmonary artery, %FEV1 forced expiratory volume in 1 s %predicted, %FVC forced vital capacity %predicted, %DLCO diffusing capacity of the lung for carbon monoxide %predicted.

Table 2 .
Hemodynamic parameters at rest (after leg raise) and peak exercise.Values are reported as mean ± standard deviation or medians (interquartile ranges).C (a-v) O 2 arteriovenous O 2 difference, ex-PH exercise pulmonary hypertension, HR heart rate, PAC pulmonary arterial compliance, PAP pulmonary arterial pressure, PAWP pulmonary arterial wedge pressure, PH pulmonary hypertension, PVR pulmonary vascular resistance, SaO 2 O 2 saturation in arterial blood, SvO 2 O 2 saturation in the pulmonary artery, VO 2 oxygen consumption, VCO 2 carbon dioxide output, R respiratory exchange ratio, VE minute ventilation.

Table 3 .
Echocardiographic parameters.Values are reported as mean ± standard deviation or medians (interquartile ranges).A late peak diastolic velocity of the mitral inflow, DcT deceleration time, E early peak diastolic velocity of the mitral inflow, e' septal mitral annular motion with the sample volume placed in the septal, ex-PH exercise pulmonary hypertension, LAD left atrial diameter, LAVi left atrium volume index, LVEF left ventricular ejection fraction, PH pulmonary hypertension, RV FAC right ventricular fractional area change, sPAP systolic pulmonary arterial pressure, TAPSE tricuspid annular plane systolic excursion, TVs' peak systolic velocity of tricuspid annulus.